Medicinal composition for the treatment of certain neuroviruses

ABSTRACT

A new pharmaceutical composition is disclosed useful in the treatment of neuroviruses and formulated as an injectable solution. The pharmaceutical composition is composed of the calcium and sodium double salt of ethylene diamine tetracetic acid, associated with calcium gluconate as a source of Ca 2+   ions, and cysteine or its HC1 salt, wherein the weight ratio of the ingredients ranges from 8-12 g to 0.3 to 1 g to 0.05 to 0.2 g respectively per 100 ml of water.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of Ser. No. 705,040 filed Feb. 25,1985, now abandoned, which was a continuation of Ser. No. 527,575, filedAug. 18, 1983, now abandoned.

FIELD OF THE INVENTION

The present invention relates to a medicinal composition for thetreatment of neuroviruses, specifically herpes Zoster and herpes (herpesSimplex).

BACKGROUND OF THE INVENTION

Certain pharmeceutical compositions are known to be effective againstherpes Zoster; the antibiotic Rifamycin or the immune stimulating agentIsoprinosine (Lesourd B, Loude, J., Meunier, P., Doumerc, P., Moulias,R., Traitement du zona ZOSTER par Isoprinosine, La nouv. PresseMedicale, Jan. 23 1982, II, No. 3, p. 191) and other chemotherapeuticcompounds such as idoxuridine (Juel Jensen B.E., Treatment of Zosterwith Idoxuridine in Dimethylsulfoxide; Result of Two Blind ControlTrials; Brit. Med. J. 1970 (4), pp 776-780; cytosine arabinoside(Pierle, l.N., Cytosine Arabinoside for Herpes Zoster, New Eng. J. Med.,1974,290, pp 404-410) and adenine arabinoside (Whitely, R.J. et al,Adenine Arabinoside Therapy for Herpes Zoster, New Eng. J. Med., 1976,294, pp 1193-1199).

Isoprinoside has a slow curvature action upon Zoster eruption; itseffect upon pain is practically insignificant. The other substances,idoxuridine, cytosine, arabinoside, and adenine arabinoside arecontraindicated on account of side effects.

The antivirotic action of several classes of chelators has beenascertained as against a large spectrum of viruses (Perrin D.D. andStunzi H., 1981 - Pharmac.Ther.22, 255) in in vitro studies or in animalstudies; even certain compounds of the class of thiosemicarbazones wereproved to be active in the prophylaxis of chicken pox in an epidemic inMadras. In our country. Gh.D.Grigorescu wrote (in 1955) thatdimercapto-propanol (DMP; BAL) is effective against herpes Zoster andagainst some other viroses (1973); however, DMP is not indicated forhuman use to the fact that the therapeutic dose is higher than the toxicdose (L.Goodman, The Pharmacological Basis of Therapeutics,1980Ed.L.Goodman, A.Gilman).

The detoxifying action of the ethylene diamino-tetracetic acid iswell-known; this product is used as an antidote in poisonings with biand trivalent metals; its mechanism of action is explained by achelating process.

The chelating action of the ethylene diaminotetracetic acid and of itssalts with various metal ions is dependent upon temperature, pH, and thespecific activity of the chelating agent expressed by the stabilityconstant of the resulting complex.

Its antiviral effect has only been proved in in vitro studies on someviral enzymes--the polymerases of viral nucleic acids and theneuraminidase of the A flu virus (Perrin D.D. and Stunzi H., 1981,Pharmac.Ther.22, 255)--whose activity was inhibited by theethylenediaminotetracetic acids thus, viruses multiplication and theirpenetration into cells was prevented; however, this chelator has notbeen as yet used in antiviral human therapy.

The prior art does not mention pharmaceuticals or medicinal compositionsmeant for antiviral therapy with the ethylene diamino tetracetic acid astheir active ingredient.

DISCLOSURE OF INVENTION

The composition as per the present invention, formulated as injectablesolution, contains the calcium and sodium salt of ethylene diaminotetracetic acid, associated with calcium gluconate as a source of Ca²⁺ions and an aminoacid (preferably cysteine) or a tripeptide(glutathion); the association ratio of the 3 ingredients is 8 . . . 12;0.3 . . . 1; 0.05 . . . 0.2.

The advantages of the preparation as per the invention are thefollowing:

the drug has a specific effect in treating herpes Zoster, and herpes(Herpes Simplex).

the use of cysteine and the ethylene diamino tetracetic acid in the formof its double salt of calcium and sodium as chelating agents provides ananti-inflammatory and trophic and antiviral effect, ensures a rapiddiffusion as well as a uniform distribution in the tissues. Since it isnot metabolized in the organism, the product is rapidly eliminated (50%within the first hour from i.p. administration and 100% within 24 hoursin rats).

the Na and Ca double salt of the ethylene diaminotetracetic acid andcysteine are toxity - free in the dosage prescribed for the abovementioned neurovirotic disorders.

See below 2 concrete examples:

EXAMPLE 1

The composition of active ingredients for 100 ml of injectable solutionas per the invention is the following:

    ______________________________________                                        Calcium and sodium salt of the                                                                        10     g                                              ethylenediamino tetracetic acid                                               Calcium gluconate       0.5    g                                              Cysteine hydrochloride  0.1    g                                              Distilled water ad      100    ml                                             ______________________________________                                    

In about 80 ml of fresh distilled water, dissolve, at 80° C., thecalcium and sodium salt of the ethylenediamino tetracetic acid and then0.5 g of calcium gluconate and 0.1 g of cysteine hydrochloride; adddistilled water to 100 ml, then filter through a Millipere filter.

Divide the filtered solution in colorless 10 ml ampoules; sterilize bykeeping in the autoclave at 120° C., for 30 minutes.

EXAMPLE 2

The composition of active ingredients for 100 ml of injectable solutionas per the invention is the following:

    ______________________________________                                        Calcium and sodium salt of the                                                                        10     g                                              ethylenediamino tetracetic acid                                               Calcium gluconate       0.5    g                                              Glutathion              0.05   g                                              Distilled water ad      100    ml                                             ______________________________________                                    

In about 80 ml of fresh distilled water, dissolve at 80° C. the calciumand sodium salt of the ethylenediamino tetracetic acid, and then 0.5 gof calcium gluconate, then add the glutathion, previously dissolved in 5ml of distilled water. Add water to 100 ml and filter through aMillipore filter.

Divide the filtered solution in colorless 10 ml ampoules; sterilize bykeeping in the autoclave at 120° C. for 30 minutes.

The injectable solution as per the invention should be intramuscularlyadministered, 10 ml in 24 hours, over a period 6-7 days.

The hypotheses on the mechanism of action of the pharmaceuticalpreparation as per this invention are based on several recent studiesthat have proved that the metal ions in the organism are both directlyand indirectly involved in the synthesis and metabolism of proteins andviral nucleic acids. The chelation of several such ions by the chelatorsin this preparation inhibits viruses multiplication through themodification of the metal ions balance.

Beside hindering the process of virus multiplication, the chelators inthe claimed pharmaceutical prepartion, also act in viral and autoimmunedisorders--such as multiple sclerosis whose etiopathology is stillunknown; they determine the fluctuation of plasma Ca²⁺, thus restoringcertain lesions of the cell membrane and implicity, certain neuronalactivities. Consequently, the drug may be also effective in checkingsuch autoaggressive processes.

The association of cysteine to ethylenediamino tetracetic acid has asynergistic effect upon the latter's chelating action, since cysteineitself has the ability to fixate electrophilic agents (cations) bu thethiolic group. Moreover, cysteine has the property to form, with sometransition metals, slightly soluble complex combinations in which thenitrogen atom is coordinatively linked to the metal.

The initial experiments on the effect of the ethylenediamino tetraceticacid associated with calcium gluconate upon certain neuroviruses haveonly pointed out a temporary restoring of the nervous influx; theassociation with cysteine has resulted in a long-lasting remission ofparalysis in multiple sclerosis, a strong anti-inflammatory and trophiceffect and an intensifying of the antiviral action.

Moreover, cysteine may reduce the mutagenic effect of some chemicalcompounds (M.Moriya, K.Kato, Y.Shirasu, Mutation Research 1978, 57, 259)and therefore prevents the mutagenic effect of the pharmaceuticalpreparation.

Reduced glutathion (γ- glutamyl-cystenyl-glycine) is a naturaltripeptide to be found in all animal and vegetable tissues; it isinvolved in the organism's defense mechanisms and considered to have ananti-mutagenic effect by protecting the nucleophilic groups, frominformational macromoleculas (DNA) against strongly electrophilicagents.

Glutathion capacity to fixate through its thiolic groups, electrophilicagents (metal cations) may be compared to a chelation mechanism.

Thus, by associating glutathion to the ethylenediamino tetracetic acid,the chelating capacity of the latter is completed and enhanced and theproduct is provided with an antimutagenic action.

In the structure of glutathion, an abnormal peptidic link can benoticed, which is similar to the structure of certain natural verystrong antibiotics (produced by bacteria) and which are considered to beendowed with an antiviral property.

Unlikely such antibiotics which are highly toxic glutathion, which is anormal multifunctional metabolite of the Human organism, and is devoidof toxicity.

We claim:
 1. A pharmaceutical composition in the form of an aqueousinjectable solution for the treatment of Herpes Zoster or Herpes Simplexsaid composition consisting essentially of:(a) the calcium and sodiumdouble salt of ethylenediamine tetracetic acid; (b) calcium gluconate;and (c) cysteine or its HCl salt, wherein the weight ratio of theingredients ranges from 8-12 g to 0.3 to 1 g to 0.05 to 0.2 grespectively per 100 ml of water.